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Welcome all seeking refuge from low carb dogma!

“To kill an error is as good a service as, and sometimes even better than, the establishing of a new truth or fact”
~ Charles Darwin (it's evolutionary baybeee!)

Friday, September 20, 2013

The Vascular Functions of Insulin

Random Replay

Was having a discussion on FB about insulin this morning and while going through some blog posts this one popped up.  I find reading some old stuff interesting at times ... this is over 3 years old.  

If someone goes on a low carb diet and this manages their hyperglycemia, this is a classic example of treating symptoms while not addressing the cause of the problem which is pancreatic beta cell dysfunction, and in the case of the T2, coupled with hepatic insulin resistance.  

What low carb doesn't do is restore normal insulin secretion and signaling, and insulin plays many roles in the body beyond glucose transport.  For one, it also assists amino acid transport (and protein synthesis) which is why the IR often have elevated circulating levels of the most insulinogenic (e.g. insulin requiring) amino acids, the BCAAs.  

This post is a flashback of some of the other things insulin does.  Further it discusses the role of NEFA in all of this ... the forgotten biomarker I think most low carbers with whacky lipids should have measured as they are likely elevated.  



Original Publish Date:  7/22/2010

Vascular function, insulin resistance and fatty acids
While insulin resistance has received a great deal of attention with respect to its role in the pathogenesis of Type II diabetes, it is now clear that insulin resistance independent of hyperglycaemia is associated with a twofold to threefold increase in the risk of cardiovascular mortality, with only 50% of the excess mortality being explained by classic cardiovascular risk factors such as blood pressure and cholesterol increases [8]. In this review, we give evidence suggesting that impairment of insulin action at the level of the vasculature contributes to the more accelerated and more severe atherosclerotic process observed in clinical states of insulin resistance [9, 10].
The emphasized statement is reason for concern.

Summary (my bullet point summary with direct quotes from the article in italics)
  • Insulin increases leg blood flow 
  • Hyperinsulinemia can increase cardiac output
  • Insulin is a vasodilator
  • Magnitude of vasodilation is related to insulin concentration and rate of glucose uptake
  • Insulin's action may be more important in capillary recruitment than bulk flow in determining rates of glucose uptake.
Thus, while the role of insulin to modulate glucose metabolism by its vascular effects has been controversial [31, 32], it has been generally accepted that insulin causes vasodilation through the release of NO from the vascular endothelium.
Endothelium-derived NO is a gas that is synthesized from the precursor L-arginine in a reaction catalysed by nitric oxide synthase and continuously released from the endothelium. NO released from the endothelium diffuses through the subendothelial space to the vascular smooth muscle where it binds to the heme group of guanylate cyclase and stimulates the generation of cyclic GMP (cGMP) which in turn leads to a reduction in intracellular Ca++ resulting in smooth muscle relaxation and vasodilation [35]. 
  • The paper lists studies that elucidate the mechanism by which insulin stimulates vasodilation.  This could be stimulating NO synthesis and/or release from the endothelium or by some action on the muscle  increasing the uptake and/or activity of NO.  To this end:
These observations suggest that insulin’s effect of vasodilating skeletal muscle vasculature is not mediated by enhanced NO action on the vascular smooth muscle but depends on increased production or release of NO or both.
Aside:  This may well be a more important stimulatory function of insulin than its role in glucose uptake.
Together, these in vivo studies indicate that insulin vasodilates skeletal muscle vasculature by a net release of endothelium derived NO (EDNO)  {...}  However, in vivo studies and vascular preparations are not able to define whther the NO release represents a direct insulin effect at the level of the endothelial cell or whether it is mediated indirectly.   However, in vivo studies and vascular preparations are not able to define whether the NO release represents a direct insulin effect at the level of the endothelial cell or whether it is mediated indirectly.

The remainder of this section of the article goes into a hypothetical mechanism.  At this point I'm not as interested in the exact nitty gritty so I'll leave reading that to anyone with greater interest.  
  • Lean non-diabetic, non-IR individuals have a dose dependent increase in leg blood flow with insulin.  Type 2 diabetics with IR have severely impaired effect - <50% of LBF increases in the lean.  
  • Obesity was associated with an intermediate response.  The obese could produce the same LBF as lean, but required much higher insulin levels to do so.
  • General Conclusion:  The most IR = most impaired vasodilatory effect of insulin
  • NO flux correlates with the degree of insulin sensitivity:  athletes > lean > obese > T2
  • PI3K is the enzyme involved.
Endothelial dysfunction in the insulin-resistant obese subjects and patients with Type II diabetic subjects might not be limited to the response to insulin but be more generalised. This notion is important because cardiovascular risk has been shown to relate to coronary endothelial dysfunction [52, 53, 54], which in turn is correlated to endothelial dysfunction in the peripheral vasculature [55]. Thus, endothelial dysfunction in obesity and Type II diabetes could explain some of the excess mortality in these insulin-resistant states [56, 57, 58, 59] which cannot be accounted for by classic risk factors such as age, cholesterol concentrations, 
blood pressure and smoking etc [8].
  • Premenopausal women have higher EDNO than males but this gender differential is cancelled out by obesity and/or T2 diabetes.
obesity and Type II diabetes induce selective insulin resistance in the PI3K signalling pathway in vascular tissue.

Taken together, simple obesity and insulin resistance are associated with marked endothelial dysfunction.  This endothelial dysfunction seems to be independent of other variables such as cholesterol, age or blood pressure that are known to modulate endothelial function. Insulin resistance induces alterations in insulin signalling within the vascular wall, which could account for reduced NO production. In turn, reduced NO action could be instrumental in accelerating the atherosclerotic disease process.
This is apparently independent of hyperglycemia.  If one loses considerable weight on a low carb diet, insulin resistance SHOULD be somewhat reversed.  But if someone fails to lose weight on an LC diet, improvements in blood glucose levels may offer false reassurances.   
Effects of non-esterified fatty acids on the vasculature and insulin sensitivity
The mechanism(s) responsible for endothelial dysfunction in insulin-resistant states are not well understood.  One of the characteristic metabolic abnormalities of insulin-resistant states is higher circulating non-esterified fatty acid (NEFA) concentrations. Importantly, under insulin-resistant conditions, NEFA concentrations are not only higher under fasting conditions but also fail to suppress appropriately in response to insulin in the postprandial state [65]. Thus, the skeletal muscle and the vasculature of insulin-resistant patients are constantly exposed to higher NEFA concentrations.
  • In rats, elevated NEFA/FFA for 5 hours reduced insulin's activation of PI3K by 90%.
  • This demonstrates that NEFA/FFA interfere with insulin signalling of PI3K.
  • Reminder:  PI3K is enzyme responsible for EDNO.
Because intact PI3K signalling is required for insulin’s effect to release endothelial NO, together these results suggest that higher amounts of NEFA could be, at least in part, responsible for the vascular abnormalities observed in clinical states of insulin resistance.
  • The article goes on to cite several studies relating NEFA/FFA to NO production, etc.  
  • Short term NEFA elevation reduces MCH NO production {going to be looking into this soon}, longer term NEFA elevation reduces insulin stimulated NO production.
  • The effects of NEFA on  NO/vasodilation again seem to be at the production/release level and not impairment of NO action.
The notion that vascular and metabolic effects of insulin could be coupled is supported by a strong correlation between NEFA-induced changes in glucose metabolism and blood flow increments (Fig. 8). Given that NEFA concentrations are constantly higher in insulin-resistant states of obesity and Type II diabetes, dysregulation of fatty acid metabolism could represent a shared and instrumental step leading to impairment of vascular reactivity and endothelial function and insulin-mediated glucose metabolism. The understanding of common and tissue specific effects of raised NEFA on insulin-receptor signalling events could identify targets for drug treatment that improve both glucose metabolism and vascular function. Improved vascular function should result in increased insulin sensitivity and decreased rates of macrovascular disease in these high-risk subjects.
This article adds to my concerns over dietary interventions in pre-diabetes.  Insulin resistance has already set in, but those diagnosed with pre-diabetes are not yet experiencing the level of insulin deficiency to see the glycemic effects.  While blood glucose levels should not be ignored, focusing treatment on them is to focus on a down-line symptom and not the underlying cause.

Insulin has been villified in the LC community and is seen, more often than not, as damaging to the body and the cause of fat accumulation.   But clearly it is insulin DEFICIENCY (direct or due to resistance to insulin's actions) that leads to a whole host of metabolic derangements and deleterious effects.   Therefore, the low carb community's near singular mission to lower insulin levels through diet seems misguided, particularly with a very high fat diet while limiting not only carbs but protein.  The strategy for stopping/reversing the course should be to increase insulin SENSITIVITY.  Here's where exercise seems  to trump diet.  The reflexive shunning of "mainstream recommended" exercise seems counterproductive here.   And if the trade-off of LC vs. HC diet is somewhat better BG control and lower insulin levels at the expense of further elevated NEFA, is this really healthier for the body in the long run?  Particularly for those who cannot lose and maintain weight loss with this WOE (and there are many).

Pre-diabetes = IR is already a metabolically dysfunctional state.  And as the introduction to the article states, increased risk of CVD is associated with the IR.  More consequences come about when glycemic control is disturbed, but IR in and of itself is a condition we should pro-actively treat so that insulin can perform its necessary and, ultimately beneficial roles in the human body.  Lowering insulin levels, or attempting to lower insulin exposure by reducing intake of insulin-provoking nutrients while putting the body in the equivalent of a fasted state (elevating NEFA/FFA) appears on its face to be counterproductive.

So what of all those examples on the net where folks were able to ditch the meds?  Being in energy deficit vs. energy surplus and losing excess fat mass is probably what is responsible for this.  If the pancreas' ability to produce insulin has not yet been compromised, this person's metabolism could conceivably revert to "normal".  Such things as fasting NEFA, blood pressure and basal insulin  are probably better indicators of that person's state of metabolic health than blood glucose readings alone.

1 comment:

Bris Vegas said...

Fortunately most Type 2 diabetics seem to achieve near-normal insulin sensitivity after 3-6 weeks of moderate exercise and a low fat calorie retricted diet.

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